It has been appreciated for some time that glial cells in the brain express neurotransmitter receptors and can respond appropriately to application of exogenous neurotransmitter. These findings are exciting in that they suggest that glial cells might sense endogenous, synaptically released neurotransmitter and thereby have th capacity to respond to neuronal activity on a millisecond time scale. Recently, it has been shown using hippocampal microisland cultures, that stimulation of a single excitatory neuron can give rise to a rapid inward current in an adjacent glial cell (Mennerick and Zorumski, Nature 368:69, 1994). However, this current was almost exclusively mediated by the activation of electrogenic glutamate reuptake, not glutamate receptors. Reports of robust receptor mediated synaptic current recorded in glia are few, and are limited to specialized synaptoid contacts in the pituitary. in the cerebellar cortex, glial cells ensheathe the parallel fiber-Purkinje neuron synmapse unusually tightly and express a high density of inotropic glutamate receptors on the plasma membrane adjacent to these synapse. This suggests that cerebellar glial cells might be unusually well positioned to detect synaptically released glutamate. Using cell pair recording in cerebellar cultures from embryonic mouse, we have found that activation of a cerebellar granule neuron can give rise to a rapid inward current in an adjacent GFAP-positive glial cell, and that this current is mediated by activation of Ca-permeable AMPA/kainate receptors and is independent of glutamate reuptake or gap junctional coupling. We propose to extend these initial findings in several ways. First, simultaneous recordings will be made from a Purkinje neuron and glial cell innervated by a single granule cell in order to compare the neuronal and glial EPSCs in terms of receptor pharmacology, kinetics, quantal parameters, and short term presynaptic plasticity (facilitation). Second, as preliminary work has shown that these glial cells respond to exogenous GABA, stimulation of inhibitory interneurons will be undertaken to determine if the glial cells can detect synaptically released GABA as well. Third, all phases of this work will be extended to the slice preparation to determine if these novel properties of cerebellar glia are present in a preparation that maintains a greater degree of morphological fidelity to the intact cerebellum. These investigations of neuron/glia signaling hold promise for deepening our basic understanding of glutamatergic and GABAergic transmission, pathologies of which include epilepsy, hypoxic/ischemic damage and diseases of memory.